No agent has been demonstrated unequivocally to have clinically significant neuroprotective efficacy in Parkinson's disease (PD) patients; that is to slow or stop the ongoing loss of dopaminergic neurons and synapses. On the other hand, numerous agents have shown clear neuroprotective efficacy in vitro and in various in vivo models of PD, providing hope that effective neuroprotection can be achieved in PID patients. Selection of agents that target mechanisms of demonstrated pathogenetic significance in PD patients will improve the likelihood that this success in vitro and in vivo will translate into similar success in PD patients. Evidence has accumulated that mitochondrial dysfunction and oxidative stress may play key roles in the pathogenesis of PD. Mitochondrial complex I activity is impaired in the substantia nigra in PD compared to age-matched controls. The ability of complex I inhibitors (MPTP and rotenone) to reproduce many features of PD when systemically administered in animals indicates that complex I dysfunction may play a causal role in PD. Levels of markers of oxidative damage to lipids, proteins, and DNA are elevated in the substantia nigra in PD (as well as in MPTP-treated animals). Thus, complex I dysfunction resulting in oxidative stress may play a key role in the pathogenesis of PD. The parallel work on the role of alpha synuclein in PD also now is revealing a strong connection to mitochondrial mechanisms. Inhibition of complex I or exposure to oxidative stress promotes alpha synuclein aggregation. Conversely, overexpression of mutant or wild-type alpha synuclein induces mitochondrial dysfunction and oxidative stress, and expression of mutant alpha synuclein enhances susceptibility to oxidative stress. In vitro and in vivo models of PD have demonstrated successful neuroprotection with strategies to enhance energy metabolism, block free radical damage, or enhance endogenous antioxidant mechanisms. The clinical trial now being planned provides a unique opportunity to determine if similar strategies can yield clinically meaningful neuroprotection in PD.